Nutrition 26 (2010) 243–249

Review article

Exenatide and weight loss

David P. Bradley, M.D., M.S.a, Roger Kulstad, M.D.b, and Dale A. Schoeller, Ph.D.c,*aDivision of Endocrinology, University of Wisconsin, Madison, Wisconsin, USA

bDepartment of Endocrinology , Marshfield Clinic–Weston Center, Weston, Wisconsin, USAcDepartment of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin, USA

Manuscript received July 9, 2009; accepted July 14, 2009.

Abstract Objective: Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone mainly released from the

www.nutritionjrnl.com

* Corresponding a

E-mail address: ds

0899-9007/10/$ – see

doi:10.1016/j.nut.2009

distal ileum, jejunum, and colon in response to food ingestion. It is categorized as an incretin due to its

activation of GLP-1 receptors in pancreatic b-cells leading to insulin exocytosis in a glucose-dependent

manner. Exenatide (synthetic exendin-4) is a subcutaneously injected GLP-1 receptor agonist that

shares 50% homology with GLP-1. It is derived from lizard venom and stimulates the GLP-1

receptor for prolonged periods. The present review aims to enumerate exenatide-instigated weight

loss, summarize the known mechanisms of exenatide-induced weight loss, and elaborate on its possible

application in the pharmacotherapy of obesity.

Methods: A search through PubMed was performed using exenatide and weight loss as search terms.

A second search was performed using exenatide and mechanisms or actions as search terms.

Results: In addition to exenatide’s action to increase insulin secretion in individuals with elevated

levels of plasma glucose, clinical trials have reported consistent weight loss associated with exenatide

treatment. Studies have found evidence that exenatide decreases energy intake and increases energy

expenditure, but findings on which predominates to cause weight loss are often inconsistent and

controversial.

Conclusion: Further research on the effects of exenatide treatment on energy intake and expenditure

are recommended to better understand the mechanisms through which exenatide causes weight loss.

� 2010 Elsevier Inc. All rights reserved.

Keywords: Obesity; Drug treatment; Glucagon-like peptide-1; Appetite; Energy expenditure

Introduction

Diabetes mellitus affects more than 245 million adults in

the world [1]. In the United States alone, over 7% of the pop-

ulation, or 23.6 million people, are affected by diabetes, with

more than 90% with type 2 diabetes [2]. In addition, there are

currently more than 57 million Americans with impaired fast-

ing glucose, or ‘‘prediabetes.’’ By 2030, even conservative

estimates have diabetes affecting more than 30 million Amer-

icans [3]. This trend is shared globally. The cost of diabetes

in 2007 was estimated to be approximately $232 billion in di-

rect and indirect medical expenses per year worldwide [1].

uthor. Tel.: þ608-262-1082; fax: þ608-262-5860.

choell@nutrisci.wisc.edu (D. A. Schoeller).

front matter � 2010 Elsevier Inc. All rights reserved.

.07.008

More than 50% of this total was spent in the United States,

accounting for 10% of the nation’s health budget [4].

The ill-toward effects of diabetes mellitus are well docu-

mented. Diabetes is the fourth leading cause of disease-related

death in the world and diabetes-related causes claim a life ev-

ery 10 s [1]. Two major trials concluding in the 1990s com-

pared the ramifications of conventional versus intensive

insulin therapy on the complications of diabetes mellitus.

All the studies had substantial and sustained lowering of he-

moglobin A1c in the study participants who underwent the in-

tensive regimen. In the Diabetes Complications and Control

Trial, lowering blood glucose reduced the risk of eye disease

by 76%, kidney disease by 50%, and clinical neuropathy by

60% [5]. In the United Kingdom Prospective Diabetes Study,

each 1% reduction in mean hemoglobin A1c was associated

with an overall risk reduction of 35% for microvascular com-

plications (retinopathy, neuropathy, nephropathy), 25%

D. P. Bradley et al. / Nutrition 26 (2010) 243–249244

reduction in diabetes-related deaths, and 18% reduction in fa-

tal and non-fatal myocardial infarction (although not reaching

statistical significance). There was a 7% reduction in all-cause

mortality [6].

Obesity, often coexistent with diabetes, increases health-re-

lated problems exponentially. The World Health Organiza-

tion’s (WHO) latest projections indicated that globally in

2005 approximately 1.6 billion adults (�15 y old) were over-

weight and at least 400 million were obese. The WHO further

projects that by 2015 approximately 2.3 billion adults will be

overweight and more than 700 million will be obese. At least

20 million children younger than 5 y were overweight in

2005. Health consequences directly engendered by obesity

can be categorized by the effects of increased fat mass (osteo-

arthritis, obstructive sleep apnea, social stigmatization, etc.) or

by an increased number of fat cells (insulin resistance leading to

type 2 diabetes, cancer, cardiovascular disease, non-alcoholic

fatty liver disease, etc.). Obesity is also related to a variety of

other complications through mechanisms sharing a common

cause such as poor diet or a sedentary lifestyle. These include

gastrointestinal reflux disease, gout, headache, cellulitis, cere-

brovascular incidents, chronic renal failure, hypogonadism,

and erectile dysfunction, among others.

The association between type 2 diabetes mellitus and

obesity is well acknowledged. In a cross sectional survey

utilizing the Behavioral Risk Factor Surveillance System in

2001, compared with adults with normal weight, adults

with a BMI of 40 or higher had an odds ratio (OR) of 7.37

(95% confidence interval [CI], 6.39–8.50) for diagnosed di-

abetes [7]. This is because diabetes and obesity are coupled

by the phenomenon of insulin resistance occurring in periph-

eral tissues and the central satiety centers of the hypothala-

mus [8]. The mechanism by which obesity fosters a state of

insulin resistance continues to be a rapidly evolving area of

interest and the subject of intense research. A full discussion

is beyond the scope of this review article. Numerous hypoth-

eses have been postulated including increased adiposity lead-

ing to decreased number of insulin receptors or a failure to

activate tyrosine kinase and phosphatidyl-inositol 3 in

response to insulin receptor binding. Other theories involve

the release of increased amounts of non-esterified fatty

acids and proinflammatory cytokines (tumor necrosis

factor-a) or increased inflammation related to macrophage

accumulation [9].

Given the high prevalence of diabetes and obesity, their

causal relation, and the multiple risks associated with either

alone or in combination, a dual pharmacologic agent attack-

ing both would obviously be of great consequence.

The incretin effect and glucagon-like peptide-1

The incretin effect was first demonstrated in the 1960s

[10]. The basic principle is that oral administration of glucose

has a greater stimulatory effect on insulin secretion than intra-

venously administered glucose [11]. In patients with type 2

diabetes mellitus this stimulation to orally administered

glucose is significantly diminished, suggesting that there

are gut-derived factors playing an important role in postpran-

dial glucose control. These gut or incretin hormones were

subsequently found to be glucagon-like peptide-1 (GLP-1),

secreted from L-cells of the jejunum, ileum, and colon, and

glucose-dependent insulinotropic polypeptide, secreted

from K-cells in the duodenum. In diabetic patients, GLP-1

concentrations are reduced in response to a meal compared

with non-diabetics. In contrast, glucose-dependent insulino-

tropic polypeptide concentrations are normal or increased,

making GLP-1 the more favorable therapeutic target [12].

The contribution of incretin hormones to the postprandial

insulin response was estimated to be 73% in control subjects

compared with 36% in type 2 diabetics, suggesting a signifi-

cant reduction of the incretin effect [13].

Numerous beneficial effects have since been ascribed to

GLP-1 (Fig. 1). The hormone has been found to act as an

incretin, thus enhancing the ability of the pancreas to release

insulin in response to ingested glucose. This insulinotropic

action of GLP-1 is glucose-dependent (as glucose approaches

normal, the effect diminishes), and for GLP-1 to enhance

insulin secretion, glucose concentrations must be higher

than 90 mg/dL, thus theoretically eliminating the risk of

hypoglycemia [14–17]. GLP-1 has also been shown to elim-

inate the inappropriate postprandial glucagon secretion that

often leads to glucose excursions after meals. However,

GLP-1 does not inhibit glucagon secretion when plasma

levels are low or normal. GLP-1 also stimulates b-cell prolif-

eration and increases b-cell mass. GLP-1 slows gastric emp-

tying, allowing the rate of glucose release to better match the

rate of glucose utilization in the systemic circulation. The

normal physiologic response to hypoglycemia is an acceler-

ation of gastric emptying, which increases nutrient delivery

and restores normal glucose concentrations. In contrast,

during hyperglycemia, the rate of gastric emptying slows,

improving the match between glucose appearance by means

of nutrient absorption from the small intestine and glucose

disappearance from the circulation. Despite hyperglycemia,

the gastric half-emptying time is significantly shorter in

patients with type 2 diabetes than in control subjects without

diabetes. The mismatch between glucose-appearance and

glucose-disappearance rates contributes to high postprandial

glucose concentrations [18]. GLP-1 slows gastric emptying

to reduce the initial postprandial increase in plasma glucose.

In addition, GLP-1 administration has been found to increase

satiety when administered peripherally and centrally, an

effect that will be described in detail later.

In line with these numerous roles, GLP-1 receptor knockout

mice have fasting hyperglycemia and abnormal glucose toler-

ance and mice lacking dipeptidyl peptidase IV (DPP-IV) show

decreased food intake, improved insulin sensitivity, and de-

creased loss of b-cell mass [19].

Native GLP-1, however, has a short half-life (1–2 min)

due to rapid N-terminal degradation by DPP-IV. Exenatide

is a 39-amino acid peptide with 53% homology to GLP-1

that is a naturally occurring component of the Gila monster

Fig. 1. Effects of GLP-1 on multiple organ systems. GLP-1 is secreted by ileal L-cells in response to a meal and has direct actions in the brain, stomach, and a- and

b-cells of the pancreas. In the brain GLP-1 acts to increase satiety. In the stomach it acts to decrease gastric emptying. Effects on a-cells of the pancreas include

decreased glucagon secretion, whereas in b-cells it leads to increased insulin secretion and decreased apoptosis. GLP-1, glucagon-like peptide-1.

D. P. Bradley et al. / Nutrition 26 (2010) 243–249 245

(Heloderma suspectum) saliva. It is resistant to DPP-IV

degradation and thus has a longer half-life with pharmaco-

logic action lasting 6 h. It reaches peak plasma concentration

at approximately 2 h. In vitro, exenatide has been shown to

bind to and activate the GLP-1 receptor of rat islet cells. It

is primarily excreted by glomerular filtration. Exenatide

decreases weight, whereas DPP-IV inhibitors are weight

neutral.

Studies of exenatide and weight loss

Three similar phase 3 trials of exenatide were performed

in patients with type 2 diabetes mellitus. All had identical

basic designs but differed in the background oral anti-glyce-

mic agent (metformin, sulfonylurea, or metformin plus sulfo-

nylurea). All three studies were blinded placebo-controlled

studies conducted over a 30-d period. In the first by Buse

et al. [20], with exenatide combined with a sulfonylurea,

377 patients were enrolled at 106 sites with changes in

body weight from baseline over time of �1.6 6 0.3 kg in

the 10-mg arm (significantly different from placebo),

�0.9 6 0.3 kg in the 5-mg arm (not significantly different

from the placebo arm), and �0.6 6 0.3 kg in the placebo

arm. In the second, by Defronzo et al. [21], combining exena-

tide with metformin, 336 patients were enrolled at 82 sites

with changes of �2.8 6 0.5 kg in 10-mg arm (P< 0.05),

�1.6 6 0.4 kg in the 5-mg arm (P< 0.001), and

�0.3 6 0.3 kg in the placebo arm. Weight loss was more

pronounced for patients with a higher body mass index.

The third study by Kendall et al. [22], combining exenatide

with a sulfonylurea and metformin, involved 733 patients en-

rolled at 91 sites, with changes of�1.6 6 0.5 kg in the 10-mg

arm (P< 0.05), �1.6 6 0.4 kg in the 5-mg arm (P< 0.001),

and�0.9 6 0.3 kg in the placebo arm. Similar results, detail-

ing progressive weight loss over time, have been seen by

numerous other investigators (Table 1) [23–29].

The predominant side effect in these studies was nausea,

which occurred in a dose-related pattern. This has led to spec-

ulation that nausea is a potential theoretical cause of the

observed weight loss. None of these initial studies, however,

showed a statistical correlation between the two. Further

studies have had conflicting results [27].

In contrast to other weight loss therapies, exenatide-in-

duced weight loss is not only progressive but persists for at

least 2 y [30].

Balance of weight

Bioenergetics is the study of the flow and transformation

of energy in and between living organisms and between liv-

ing organisms and their environment [31]. According to the

first law of thermodynamics, energy can neither be created

nor destroyed, only transformed from one form to another.

Thus, in accordance with this basic principle, the bioenerget-

ics of the human body can be measured as a balance between

two competing facets: energy intake and energy expenditure.

Table 1

Randomized control trials of exenatide with concomitant therapy, frequency of nausea, and amount of weight loss

Study Duration of study Concomitant therapy Frequency of nausea (%) Weight loss (kg)

Placebo 5-mg dose 10-mg dose 5-mg dose 10-mg dose

Buse et al. [20] 30 wk Sulfonylurea 7 39 51 0.9 1.6

Defronzo et al. [21] 30 wk Metformin 23 36 45 1.6 2.8

Kendall et al. [22] 30 wk Metformin þ sulfonylurea 21 39 49 1.6 1.6

Heine et al. [23] 26 wk Metformin þ sulfonylurea 8.6 57 N/A 2.3 N/A

Davis et al. [26]* 16 wk None 12.5 N/A 48.5 N/A 4.2

Barnett et al. [27]* 16 wk Metformin or sulfonylurea 3.1 N/A 42.6 N/A 0.8

Zinman et al. [28] 16 wk Thiazolidinedione 15.2 N/A 40 N/A 1.51

Nauck et al. [29]* 52 wk Metformin þ sulfonylurea 0.4 N/A 33 N/A 2.5

N/A, not available

* Studies administered exenatide 5 mg two times daily for 4 wk and then 10 mg two times daily until completion.

D. P. Bradley et al. / Nutrition 26 (2010) 243–249246

Energy intake is composed of the caloric contents of ingested

food, whereas energy expenditure is composed of three

subsets: the resting metabolic rate (RMR), defined as the en-

ergy required for maintenance of normal bodily functions

such as respiration, circulation, and body temperature; the

thermic effect of a meal, defined as the energy expended

above RMR due to absorption, metabolism, and storage of

dietary nutrients; and the physical activity energy expendi-

ture, defined as the energy expended from physical activity,

which includes exercise and activities of daily living. The

components and their relative contributions to total energy

expenditure can be seen in Figure 2.

Bioenergetics and exenatide

Sustained progressive weight loss is an objective in

obesity and insulin resistance-related diabetes mellitus.

Therefore, mechanisms to aid in this process are constantly

under investigation. Most studies to date have examined

the role of GLP-1 and exenatide in the reduction of oral in-

take. Edwards et al. [32] found that healthy volunteers con-

sumed 19% fewer calories at a free-choice buffet lunch

Fig. 2. Components of total energy expenditure by approximate percentage.

PAEE, physical activity energy expenditure; RMR, resting metabolic rate;

TEM, thermic effect of a meal.

after intravenous infusion of exendin-4. Other studies have

echoed this effect on decreased oral intake. A meta-analysis

of seven studies on ad libitum energy intake after intravenous

GLP-1 infusion showed that energy intake decreased by 727

kJ, or 11.7% [33]. This finding in human subjects, however,

was challenged by the observation that GLP-1 receptor–

deficient mice have normal intake and body weight [34].

The anorectic effects of GLP-1 are not well understood.

The regulation of feeding and energy balance involves

hormonal and neural inputs and is quite complex. The phys-

iologic role of GLP-1 and the mechanism responsible for

weight loss with adjunctive exendin-4 are an area of consid-

erable research.

Possible mechanisms to explain the observed decrease in

oral intake include exenatide-induced nausea, decreased

gastric emptying, and increased satiety. Although nausea is

common with exenatide use and may singularly lead to

decreased intake, studies have failed to demonstrate a correla-

tion between the presence of, or the degree of, nausea and

lowering of body weight.

In addition, decreased oral intake with exenatide may

involve the ‘‘ileal brake’’ and its relation to retarded gastric

emptying. The ileal brake is the primary inhibitory feedback

mechanism, neural and hormonal, to control transit of a meal

through the gastrointestinal tract to optimize nutrient diges-

tion and absorption. Ingested food activates distal intestinal

signals that inhibit gastrointestinal motility and thus prolong

emptying. This effect is thought to be mediated by vagal

efferent nerves, activated by gastric distention and gastroin-

testinal hormones, that are transmitted to the solitary nucleus

of the brainstem [35]. In fact, GLP-1–induced anorexia is

abolished by vagal transection [36]. The rate of gastric emp-

tying is a key determinant of glucose levels after a meal and is

often abnormal and frequently accelerated in individuals with

diabetes [37–39]. This acceleration disrupts the ileal brake.

GLP-1 slows gastric emptying to reduce the initial postpran-

dial increase in plasma glucose.

Another possible mechanism involves increased satiety.

The GLP-1 receptor is mainly distributed in the pancreatic

islets and gastric glands [40], but has also been found in

D. P. Bradley et al. / Nutrition 26 (2010) 243–249 247

various regions of the central nervous system [41] with

a wide distribution throughout the rostrocaudal extent of

the hypothalamus and, in particular, dense accumulations

in the paraventricular and arcuate nucleus [42]. This area

has been found to be crucial to the regulation of appetite. Di-

rect administration of GLP-1 into the central nervous system

or transmission to the hypothalamus after peripheral admin-

istration by the vagus nerve appears to result in decreased ca-

loric intake. The appearance of c-fos expression, a marker of

GLP-1 activating the neuron, after intracerebroventricular

injection of GLP-1 provides evidence that GLP-1–induced

anorexia may be at least partly mediated by the central hypo-

thalamus. Schick et al. [43] first reported reduction of food

intake after intracerebroventricular injection of GLP-1 to

rats in 1992. The first evidence of the effect of GLP-1 on

feeding behavior in humans was reported in 1998 by Flint

et al. [44], who found increased feelings of satiety and full-

ness and reduced feeling of hunger after intravenous admin-

istration of GLP-1. Studies of exenatide relating to satiety

have similarly demonstrated an increased sense of fullness

and reduced sensation of hunger.

A summary of the effects of GLP-1 on appetite, feeding

behavior, and body weight in humans is presented in Table 2.

Glucagon-like peptide-1 and exenatide have also been

shown to result in decreased levels of ghrelin, a potent orexi-

genic hormone [45]. The extent to which ghrelin and its inter-

action with other satiety factors contributes to weight loss is

unknown.

In terms of energy expenditure, there are limited studies to

this point. Energy expenditure can be assessed in a variety of

Table 2

Current studies of effects of glucagon-like peptide-1 on appetite, feeding behavior

References Dose (pmol $ kg�1 $ min�1) Duration

Flint et al. [44] 0.7 4 h

Gutzwiller et al., 1999 [50] 0–1.5 2 h

Toft-Nielsen et al., 1999 [51] 2.4 48 h

Hellerstrom et al., 1999 [52] 0.75 8 h

Zander et al., 2001 [53] 2.4 6 wk

IV, intravenous; SC, subcutaneous

ways. Most data are accumulated from indirect resting calo-

rimetry. Indirect calorimeter studies estimate heat production

from measurements of oxygen consumption and carbon

dioxide production while a subject is enclosed in a ventilated

hood. It allows measurements of the RMR and the thermic

effect of a meal but does not provide a free-living environ-

ment for which to measure physical activity (physical activity

energy expenditure) and thus does not allow for a calculation

of total energy expenditure. This technique has been utilized

by several investigators. Shalev et al. [46] found that GLP-1

infusion increased RMR. Flint et al. [47,48] reported that

GLP-1 infusion also increased RMR and resulted in a de-

creased thermic effect of a meal in non-obese and obese

patients. Pannacciulli et al. [49] similarly found that GLP-1

increased short-term RMR after adjusting for age, sex, and

body composition.

The global burden of obesity and diabetes has accelerated

research into the development of a large number of pharma-

cologic agents that target excess weight or insulin action.

Among those agents that have reached market, exenatide is

interesting because it acts to stimulate insulin production as

intended, but also has been found to cause weight loss. It is

not clear, however, how much of the weight loss is due

to an incretin effect on energy intake or expenditure. The lat-

ter has been difficult to access until the development of

methods for measuring energy expenditure in free-living

subjects. To date, there are to our knowledge no published

studies that provide information regarding total energy ex-

penditure after exenatide administration, although several

are ongoing and will likely provide further clarification

, and body weight in humans

Route Subjects Effects P

IV 20 healthy Reduction of energy

intake 21%

0.0002

Decreased sensation

of hunger

0.012

Enhanced fullness 0.028

Enhanced satiety 0.013

IV 16 healthy Reduction of food

intake 35%

<0.001

Reduction of caloric

intake 32%

<0.001

Reduction of fluid

intake 18%

<0.01

SC 6 diabetics Decreased feeling

of hunger

<0.05

Decreased future

food intake

<0.05

Fullness not affected —

IV Obese Reduced caloric intake —

Reduced sensation

of hunger

—

SC 10 diabetics Reduction of body

weight 1.9%

0.02

Reduction of appetite 21% 0.01

D. P. Bradley et al. / Nutrition 26 (2010) 243–249248

regarding exenatide’s effects on energy expenditure. Under-

standing these effects of exenatide may provide clues for

treatment of obesity using this drug or developing drugs

that have similar actions.

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